DJ-1 suppresses ferroptosis through preserving the activity of S-adenosyl homocysteine hydrolase
DJ-1 suppresses ferroptosis through preserving the activity of S-adenosyl homocysteine hydrolase
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DJ-1 通过保留 S-腺苷同型半胱氨酸水解酶的活性来抑制铁死亡
DOI：
10.1038/s41467-020-15109-y
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发表时间：
2020-03-06
影响因子：
16.6
通讯作者：
Ying, Meidan
中科院分区：
文献类型：
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作者：
Cao, Ji;Chen, Xiaobing;Ying, Meidan
铁下垂是一种由铁依赖的脂质活性氧蓄积介导的调节性细胞死亡的新的特征形式，具有巨大的癌症治疗潜力。然而，铁性下垂的分子机制在很大程度上仍然难以捉摸。在这项研究中，我们定义了DJ-1在铁性下垂中的整合作用。抑制DJ-1在体外和体内都能有效地增强肿瘤细胞对铁下垂诱导剂的敏感性。代谢分析和代谢物挽救分析表明，DJ-1的耗竭通过破坏S-腺苷同型半胱氨酸水解酶四聚体的形成并降低其活性来抑制跨硫途径。因此，当同型半胱氨酸的生成减少时，会导致更多的铁下垂，这可能是半胱氨酸摄取受阻时谷胱甘肽生物合成的唯一来源。因此，我们的发现表明，DJ-1决定了癌细胞对铁下垂的反应，并突出了潜在地改善基于铁下垂的抗肿瘤治疗效果的候选治疗靶点。
Ferroptosis is a newly characterized form of regulated cell death mediated by iron-dependent accumulation of lipid reactive oxygen species and holds great potential for cancer therapy. However, the molecular mechanisms underlying ferroptosis remain largely elusive. In this study, we define an integrative role of DJ-1 in ferroptosis. Inhibition of DJ-1 potently enhances the sensitivity of tumor cells to ferroptosis inducers both in vitro and in vivo. Metabolic analysis and metabolite rescue assay reveal that DJ-1 depletion inhibits the transsulfuration pathway by disrupting the formation of the S-adenosyl homocysteine hydrolase tetramer and impairing its activity. Consequently, more ferroptosis is induced when homocysteine generation is decreased, which might be the only source of glutathione biosynthesis when cystine uptake is blocked. Thus, our findings show that DJ-1 determines the response of cancer cells to ferroptosis, and highlight a candidate therapeutic target to potentially improve the effect of ferroptosis-based antitumor therapy.